Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia.

ABSTRACT: Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1? transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1? double transgenic mice had half as many metaplastic nodules as control L2-IL-1? mice. This effect was not due to a reduction in esophageal IL-1? mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2::L2-IL-1? mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1? mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2::L2-IL-1? mice is CD8+ T cell dependent, which CD11b+Gr-1+ cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+ cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2::L2-IL-1? double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+ cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+ immature myeloid cells.

SUBMITTER: Kong J 

PROVIDER: S-EPMC4741744 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature